To determine the safety and tolerability of IV and oral levetiracetam monotherapy for seizures in brain tumor patients following resection. Brain tumor patients undergoing neurosurgery with >or=1 seizure within the preceding month prior to surgery were enrolled to receive intravenous levetiracetam for a minimum of 48 h, transitioned to oral levetiracetam at the same dose, and followed for 1-month after discharge. Patients were assessed daily in the hospital, provided with a seizure diary, and supplied with 30 days of levetiracetam upon discharge. Study patients were telephoned weekly to assess their cognitive status and seizure frequency. Of the 17 patients enrolled, the baseline seizure types were tonic clonic, partial, and complex partial with secondary generalization. The most common type of tumor was glioblastoma multiforme. Levetiracetam was well tolerated with no medication discontinuation during the study period. Adverse effects reported were somnolence, nausea/vomiting, headache, and insomnia. Eleven patients were evaluable for TICS scores (64.7%) with an average score of 33.3. Two patients were deemed to be cognitively impaired (18.2%). Eleven of twelve patients (91.7%) that completed the study period achieved a >or=50% reduction in their number of seizures. A total of 92 drug interactions were avoided (P = 0.0016) with dexamethasone, acetaminophen, and fentanyl being the most common. Levetiracetam monotherapy was found to be safe and tolerable in this patient population. Nearly all patients achieved a >or=50% reduction in seizure frequency post-op with levetiracetam monotherapy. Levetiracetam also has the potential for less drug interactions compared to phenytoin in these patients.